1. Field of Invention
The present invention relates to a precursor of a radioactive agent for treatment of liver cancer and a manufacturing method thereof, especially to H3LMN series compounds applied to radiation therapy for liver cancer and a manufacturing method thereof.
2. Description of Related Art
Liver cancer is one of the most common causes of death nowadays. According to data from Department of Health, R.O.C, 7809 people died for liver cancers in 2007. Thus the prevention and therapy of liver cancers are important issues in domestic medical research. Conventional ways of treatment for hepatoma includes surgery, chemical therapy and radiation therapy. However, the overall cure rate remains unsatisfied. There is an urgent need to find out other effective alternatives.
Lipiodol is an iodized Poppy-seed oil. Domestic or foreign studies all demonstrate that liver cancer tissues have significant intake of lipiodol. Some researchers tried to label lipiodol with radioisotope such as I-131, Y-90 and Re-188 so as to get therapeutic agents used for radiation therapy of liver cancers. In European, 131I-Lipidol is available for liver cancer therapy. Yet the iodine-131 emits high energy gamma rays and delivers a higher total dose. Moreover, the I-131 is expensive. Thus its applications are limited. As to rhenium-188, it is a nuclide that emits both beta (βmax=2.12 Mev) and gamma rays (γ=155 KeV) and having a half-life of 16.9 h. Rhenium-188 is a very potential radioisotope for disease diagnosis and therapy because Re-188 is a generator-produced radioisotope easy to be obtained, with proper radioactive energy and short half-life. It is expected Re-188 will play an important role in radiation therapy for cancer. Therefore, lipiodol with Re-188 may be an effective therapeutic agent for radiation therapy of liver cancers.
188Re-DD has high lipophilicity and initial uptake in liver cancer is high. However, retention of 188Re-DD in liver tumors is low. This can be explained by a paper—Y. S. Lee, J. M. Jeong, Y. J. Kim, et al., Nucl. Med. Commu., 23, 237-242 (2002), through a proton transfer, 188Re-DD in cell fluid forms a cation that is hydrophilic and is easy to be released from cells, as shown in FIG. 1. Thus the retention of 188Re in liver cancer cells is far more less than expected.
Moreover, refer to C. H. Lin, F. L. Liao, S. L. Wang., Synth. React. Inorg. Met.-Org. Chem. 27(8), 1167-1182 (1997), after complex reaction of N-(1-carboethoxy-2-thioethyl)[N-(2-thioethyl)amino]aceta-mide (H4L) with ReO(PPh3)2Cl3, two compounds are obtained. As shown in FIG. 2, ReOHL is electrically neutral while ReOL is an anion carrying a negative charge. Obviously, ReOL is resulted from loss of a proton of ReOHL. Based on this experiment, it is believed that 188Re-DD in body fluid may lose a proton to yield a water-soluble anion.
Thiols are also relatively easy to oxidize under neutral or alkaline conditions, especially dithiol molecules. Oxidation of the thiol group yields a disulfide (S—S) bond. Once the S—S bond forms, there is no formation of a S-M (M=Tc or Re) bond. That means the thiol groups are unable to be applied to preparation of therapeutic agents for liver cancer.
DADT (diamide dithiol) and BAT (bis-aminoethanethiol) are frequently used organic ligands that bind with technetium (Tc) or rhenium (Re) to form complexes (coordination compounds), as shown in FIG. 3A and FIG. 3B (M=Tc or Re).
Thus the compounds of the present invention can release three protons from amines, amides and thiols during complex reactions with MO3+ (M=Tc or Re) and the complexes formed are electrically neutral. Such complexes with good lipophilicity resulted from long-chain alkyl group contained are easily soluble in lipiodol. Therefore, the complexes can be used as effective radioactive therapeutic agents for liver cancers.